What labs are recommended for a patient with a history of Restless Legs Syndrome (RLS) for primary care follow-up?

Laboratory Testing for Primary Care Follow-Up in Restless Legs Syndrome

For a patient with established RLS, order serum ferritin, transferrin saturation, complete blood count (CBC), comprehensive metabolic panel (electrolytes/renal function), TSH, and HbA1c at primary care follow-up. 1

Essential Iron Studies (Highest Priority)

Check serum ferritin and transferrin saturation in all patients with clinically significant RLS, drawn in the morning after avoiding iron-containing supplements for at least 24 hours. 1 This timing is critical because:

• Ferritin has diurnal variation and recent iron intake can falsely elevate results 1
• Inflammation can raise ferritin independent of true iron stores, making transferrin saturation essential to identify functional iron deficiency 1
• Supplement if ferritin ≤75 ng/mL or transferrin saturation <20%, which are RLS-specific thresholds that differ from general population guidelines 1
• Consider IV iron if ferritin is between 75-100 ng/mL 1, 2

The pathophysiology of RLS involves reduced CNS iron stores and impaired dopamine transport in the substantia nigra, making iron assessment fundamental to management 3, 4

Complete Blood Count

• A CBC is reasonable to assess for iron-deficiency anemia, which is a well-established secondary cause of RLS with significantly higher prevalence in affected patients 1
• This identifies overt anemia that may require more aggressive iron repletion 1
• Critical caveat: Neurological symptoms from B12 deficiency can present without hematological abnormalities—approximately one-third of B12 deficiency cases lack macrocytic anemia, so a normal CBC does not exclude B12 deficiency as a contributor 3

Metabolic and Endocrine Screening

Order a comprehensive metabolic panel (electrolytes/renal function), TSH, calcium, and HbA1c as part of the standard workup: 1

• Renal function identifies chronic kidney disease and end-stage renal disease, which are secondary causes of RLS with increasing prevalence with age 1, 3
• TSH screens for thyroid dysfunction as part of standard endocrine assessment 1
• HbA1c screens for diabetes mellitus, which has been associated with RLS and can cause peripheral neuropathy that mimics or coexists with RLS 1
• Calcium is included in baseline metabolic assessment, particularly relevant given rare case reports of hyperparathyroid-related RLS 5

Additional Considerations for Differential Diagnosis

• Urine albumin-to-creatinine ratio should be obtained to assess for renal disease if not already done 1
• Blood pressure assessment should be performed as part of cardiovascular screening 1
• Vitamin B12 level should be strongly considered, especially in patients with late-onset RLS (fifth to seventh decade) without family history, as B12 deficiency causes demyelination and axonal degeneration that produces symptoms overlapping substantially with RLS 3

Clinical Pitfalls to Avoid

Do not order polysomnography or periodic limb movement studies as part of routine RLS follow-up—these should be reserved for cases where the diagnosis is uncertain or when assessing treatment response in research settings. 1

Ensure proper timing and preparation for iron studies: Morning draw after 24-hour avoidance of iron supplements is non-negotiable to avoid false results that could lead to inappropriate management decisions. 1

Remember that end-stage renal disease patients require different treatment algorithms, so identifying renal dysfunction changes the entire management approach. 1